Patients with the genetic syndrome Neurofibromatosis type 2 (NF2) develop multiple intracranial and spinal tumors, including vestibular schwannomas (VS) and meningioma that lead to morbidity and early mortality. These tumors are the defining criteria for NF2, but are also among the most common brain tumors worldwide in non-NF2 patients. There are no known effective medical therapies for either VS or meningiomas. This proposal brings together a multi-institutional team of leading clinical and basic science experts in VS, meningiomas and NF2 to test the hypothesis that the mTOR (mammalian target of rapamycin) inhibitor RAD001 reaches meaningful intratumoral concentrations and shows evidence of mTOR pathway inhibition as well as biological activity in VS and meningioma in patients. VS and meningiomas are deficient in the protein Merlin, the gene product of the NF2 gene. Merlin deficiency may result in abnormal activation of the mTOR molecular signaling pathway and that inhibition of mTOR may stop tumor growth. We therefore hypothesize that treatment with mTOR inhibitors, such as RAD001, may be effective in the treatment of patients with VS and meningiomas. RAD001 is a well-tolerated oral drug with a favorable safety profile and anti-tumor activity against several types of cancer. It has recently shown remarkable efficacy in a genetic tumor syndrome similar to NF2 called Tuberous Sclerosis. In other tumor types, such as malignant cancers with Merlin loss, the anti-tumor efficacy of RAD001 may be limited due to disinhibition of a feedback mechanism, leading to the upregulation of AKT. At the present time, we do not know if this escape mechanism is operational in VS and meningiomas in vivo. To assess the intratumoral activity of RAD001 in patients in vivo, participants with and without NF2 scheduled for resection of a VS or meningioma who agree to participate, will take RAD001 for 7 days preceding surgery. At the time of surgery, blood and tumor tissue will be collected. RAD001 levels in the blood and tumor will be analyzed. We will also assess the effects of the drug on mTOR pathway signaling and tumor growth within the tumor cells and local parenchyma. The results of this study will provide important biological data that will inform further, rational development of mTOR-targeted therapies in VS and meningiomas. If biologically active drug concentrations of RAD001 that inhibit the primary molecular drug target can be achieved in VS and meningiomas, further development of RAD001-based therapies is warranted. If we find molecular escape mechanisms to be operational, combination therapies, such as combined mTOR and PI3K/AKT blockade should be explored. The identification of an effective medical therapy for VS and meningiomas would represent a breakthrough in neuro-oncology and enhance the quality of life and survival in patients with these tumors. PUBLIC HEALTH RELEVANCE: Vestibular schwannomas (VS) and meningiomas are among the most common intracranial tumors, and most patients currently require surgery and/or radiotherapy, resulting in significant acute and long-term morbidity. Laboratory data suggests that RAD001, a molecular targeted drug inhibiting the mTOR signaling pathway, may be effective in the treatment of patients with VS and meningiomas. We will study surgical specimens from patients who require surgery for VS or meningioma and consent to taking a 7-day course of RAD001 immediately prior to surgery. We expect that the results of this study will yield critical information on the mTOR pathway biology in patients VS and meningiomas and will enable us to rationally develop and optimize molecular targeted therapies for this population.